Bladder cancer is the fifth most common cancer in the United States. Over 70 - 80% of patients initially present with non-muscle invasive bladder cancer (NMIBC) confined to the mucosa of the bladder. These patients are treated by tumor resection followed by intravesical chemotherapy or Bacillus Calmette-Gurin (BCG) therapy. Despite treatment, 60% of NMIBC patients will experience tumor recurrence and, of these, ~30% will progress and succumb to their disease while another 50% will undergo radical cystectomy in an attempt at disease control. Since the FDA has not approved a drug for NMIBC in the last 20 years, novel therapies are desperately needed for NMIBC to prevent disease progression and allow bladder preservation. NMIBC is also the costliest of all cancers to treat due to its high recurrence rate. Thus, any effective drug for NMIBC will have a large impact on healthcare costs. Although the mechanisms leading to BCG-mediated efficacy are unclear, T cells and natural killer (NK) cells have been implicated as critical mediators of the antitumor immune response. Interleukin-15 (IL-15), previously considered by the NCI as the most promising immunotherapeutic that could potentially cure cancer, is a crucial factor for effector NK cell and CD8+ memory T cell proliferation and activation with high potency against established tumors in various animal models. To construct an improved version of IL-15, we have isolated a novel proprietary IL-15 superagonist mutant and associated it with an IL-15 receptor -Fc fusion protein to generate a complex (referred to as ALT- 803) with enhanced pharmacokinetic (PK) and immunostimulatory properties. These significant improvements have recently led NCI to promote ALT-803 over native IL-15 as its top immunotherapeutic clinical candidate against cancer. We postulate that intravesical treatment of ALT-803 in combination with BCG will induce durable cell-mediated immune responses providing antitumor efficacy in patients with NMIBC. During the SBIR Phase I project, we found that in rodent NMIBC tumor models, intravesical ALT-803 could stimulate immune responses in the bladder leading to antitumor activity. Moreover, ALT-803 + BCG immunotherapy provided significantly greater efficacy than BCG monotherapy against carcinogen-induced NMIBC. These studies suggest that ALT-803 + BCG is a more effective treatment than BCG alone and provide a strong rationale for testing intravesical ALT-803 + BCG therapy in patients with NMIBC. To support such trials, we have completed non-clinical studies and ALT-803 clinical product manufacture allowing FDA acceptance of an IND for ALT-803 testing in patients with solid tumors. Under this SBIR Phase II proposal, we plan to conduct a dose escalation phase of a multicenter Phase 1/2 study to investigate the safety, PK, and immunostimulatory and clinical activities of intravesical ALT-803 + BCG treatment in patients with NMIBC. Successful outcomes in this study will pave the way for further evaluation of intravesical ALT-803 therapy in patients with NMIBC with the ultimate goal of developing more durable or curative therapies for BCG-nave and/or BCG-refractory patients.